Technical Field
The present invention relates to pharmaceutical compounds. More specifically, the present invention relates to platinum(II) complexes having thione ligands. The present invention includes the use of these platinum(II) complexes for treatment of cancers and cell proliferative disorders.
Description of the Related Art
The “background” description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description which may not otherwise qualify as prior art at the time of filing, are neither expressly or impliedly admitted as prior art against the present invention.
Since the discovery of the platinum-based drug cisplatin, its clinical use has been reduced by its severe side effects such as nephrotoxicity and gastrointestinal effects, and also by the resistance of cancer cells to the drug [B. Rosenberg, L. VanCamp, and T. Krigas, Nature, 205 (1965) 698; M. Goren, R. Wright, and M. Horowitz, Cancer Chemoth. Pharm., 18 (1986) 69; L. R. Kelland, G. Abel, M. J. McKeage, M. Jones, P. M. Goddard, M. Valenti. B. A. Murrer, and K. R. Harrap, Cancer Res., 53 (1993) 2581—each incorporated herein by reference in its entirety]. As a result, several alternative platinum complexes have been synthesized in order to overcome these side effects. Platinum(II) complexes that have the classical structure cis-[PtX2(NHR2)2], in which X=leaving group and R=organic fragment, are found to bind to the DNA through 1,2-intrastrand cross-links, between N7 atoms of two adjacent guanine (G) with platinum(II) ion [X. Wang and Z. Guo, Chem Soc Rev 42 (2013) 202; N. Muhammad and Z. Guo, Curr Opin Chem Biol 19 (2014) 144; J. S. Butler and P. J. Sadler, Curr Opin Chem Biol 17 (2013) 175—each incorporated herein by reference in its entirety].
The search for a new generation of platinum(II) complexes, which are able to broaden the biological activity spectrum and eliminate the multifactorial drug resistance, resulted in the synthesis of structurally novel platinum(II) complexes containing biologically active ligands. These complexes are supposed to interact with the DNA through a mechanism different from that of cisplatin. Studies found that cisplatin-like drugs could introduce nephrotoxicity due to their reaction with sulfur-containing amino acids of the proteins: cysteine and methionine [J. S. Butler and P. J. Sadler, Curr Opin Chem Biol 17 (2013) 175—incorporated herein by reference in its entirety]. Platinum(I) complexes with sulfur-containing ligands, like dimethyl sulfoxide, dimethyl sulfide, xanthate and thiosemicarbazones have already shown high efficacy against some human cancer cell lines [A. Muscella, N. Calabriso, S. A. De Pascali, L. Urso, A. Ciccarese, F. P. Fanizzi, D. Migoni, and S. Marsigliante, Biochem. Pharm., 74 (2007) 28; W. Friebolin, G. Schilling, M. Zöller, and E. Amtmann, J. Med. Chem., 47 (2004) 2256; A. A. Ali, H. Nimir, C. Aktas, V. Huch, U. Rauch, K.-H. Schäfer, and M. Veith, Organometallics, 31 (2012) 2256—each incorporated herein by reference in its entirety].
Thiourea and its derivatives as sulfur-containing ligands are expected to give better results if they coordinate with the platinum(II) ion. They have been routinely used as antifungal agents, rescue agents against nephritic side effects during cisplatin administration, and as inhibitors of HIV-1 and HIV-2 reverse transcriptases [R. del Campo, J. J. Criado, E. Garcia. M. a. R. Hermosa, A. Jiménez-Sánchez, J. L. Manzano, E. Monte. E. Rodríguez-Fernández, and F. Sanz, J. Biol. Inorg. Chem., 89 (2002) 74; J. Ren, J. Diprose, J. Warren. R. M. Esnouf, L. E. Bird, S. Ikemizu. M. Slater, J. Milton. J. Balzarini, D. I. Stuart, and D. K. Stammers, J. Biol. Chem., 275 (2000) 5633—each incorporated herein by reference in its entirety]. Platinum(II) complexes with thiourea ligands demonstrated that they can bind to the DNA in a different mechanism to that of cisplatin and showed excellent cytotoxicity against ovarian and leukemia cancer cell lines [Z. Ma, L. Rao, and U. Bierbach, J. Med. Chem., 52 (2009) 3424; J. M. Brow, C. R. Pleatman, and U. Bierbach, Bioorg. Med. Chem. Lett., 12 (2002) 2953—each incorporated herein by reference in its entirety].
New platinum(H) complexes with thiourea derivatives were synthesized and characterized in order to provide compounds having improved treatment activity for cancers and cell proliferative disorders.